Recently, there have been studies concerning the endogenous production and the many physiological functions of carbon monoxide. Many studies have looked at the roles of carbon monoxide in the immune, respiratory, reproductive, gastrointestinal, kidney and liver systems. Delivery of exogenous carbon monoxide has found applications in many health research fields and clinical settings. For example, studies have shown that inhaled carbon monoxide protects tissue against several types of injuries, such as ischemia/reperfusion injuries associated with transplants. Other studies are aimed at finding innovative, preventative, and therapeutic strategies based on the physiological effects of carbon monoxide.
Several methods of manufacturing carbon monoxide exist. A process using dehydrating formic acid and a dehydrating agent is of interest. (“Pure Carbon Monoxide for Experimental Purposes,” April 1929, Industrial and Engineering Chemistry, 21, 4: 389-390. Concentrated formic acid (around 85% NF Grade) is continuously fed into phosphoric acid (about 85% concentration, heated to the vicinity of 170° C.). The gaseous products of the reaction, carbon monoxide and steam, are then led to a water-cooled condenser to dry the carbon monoxide gas, which is then scrubbed using dilute caustic soda solution to remove traces of acid fumes. Analyses of the dried carbon monoxide gas show 99.9% carbon monoxide or better. The gas was then compressed into cylinders for storage. However, traces of impurities, such as carbonyls and carbon dioxide, were present in the gas after compression.
FDA standards for 99.99% pure carbon monoxide require manufacturing in compliance with current good manufacturing practices (GMP) in a validated process. The carbon monoxide gas must also be virtually free of all impurities, including trace amounts of carbonyl and carbon dioxide. To be approved by the FDA as an active pharmaceutical ingredient (API) GMP compliance must be achieved.
For gases, US FDA Title 21 CFR Parts 210 and 211 are applicable to assure batch uniformity and integrity of the drug product. API manufacturers need also comply with ICH guideline Q7, which has been harmonized with the GMP guide created by the International Conference on Harmonization, adopted throughout the European Union, Japan and the USA.